CN104130124A - β-榄香烯13位衍生物及其治疗动脉粥样硬化的用途 - Google Patents

β-榄香烯13位衍生物及其治疗动脉粥样硬化的用途 Download PDF

Info

Publication number
CN104130124A
CN104130124A CN201410376842.7A CN201410376842A CN104130124A CN 104130124 A CN104130124 A CN 104130124A CN 201410376842 A CN201410376842 A CN 201410376842A CN 104130124 A CN104130124 A CN 104130124A
Authority
CN
China
Prior art keywords
acid
elemi
alcohol ester
compound
bases
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201410376842.7A
Other languages
English (en)
Inventor
尚靖
徐进宜
许海
王若妍
陈继超
段文丽
白仁仁
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
DALIAN YUANDA PHARMACEUTICAL TECHNOLOGY AND DEVELOPMENT Co Ltd
Original Assignee
DALIAN YUANDA PHARMACEUTICAL TECHNOLOGY AND DEVELOPMENT Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by DALIAN YUANDA PHARMACEUTICAL TECHNOLOGY AND DEVELOPMENT Co Ltd filed Critical DALIAN YUANDA PHARMACEUTICAL TECHNOLOGY AND DEVELOPMENT Co Ltd
Priority to CN201410376842.7A priority Critical patent/CN104130124A/zh
Publication of CN104130124A publication Critical patent/CN104130124A/zh
Priority to PCT/CN2015/075315 priority patent/WO2016015479A1/zh
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/225—Polycarboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/618—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
    • C07C201/06—Preparation of nitro compounds
    • C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/12—Acetic acid esters
    • C07C69/14—Acetic acid esters of monohydroxylic compounds
    • C07C69/145—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/22—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety
    • C07C69/24—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety esterified with monohydroxylic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/34—Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/40—Succinic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/34—Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/42—Glutaric acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/587—Monocarboxylic acid esters having at least two carbon-to-carbon double bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
    • C07C69/618—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety having unsaturation outside the six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/62—Halogen-containing esters
    • C07C69/65—Halogen-containing esters of unsaturated acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/78—Benzoic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C07C69/88—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with esterified carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C07C69/92—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with etherified hydroxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明涉及有机合成和药物化学领域，具体涉及一类β-榄香烯13-位衍生物(I)或(II)，其中R1和R2的定义同说明书。本发明还公开了这些β-榄香烯13-位衍生物的制备方法及其在抗动脉粥样硬化方面的应用。

Description

β-榄香烯13位衍生物及其治疗动脉粥样硬化的用途
技术领域
本发明涉及有机合成和药物化学领域，具体涉及一类β-榄香烯13-位衍生物，本发明还公开了这些β-榄香烯13-位衍生物的制备方法及其在抗动脉粥样硬化方面的应用。
背景技术
心脑血管疾病包括冠状动脉性疾病和卒中，是全球主要的致死性疾病，近年来随着人们生活水平的不断提高和饮食习惯的改变，其发病率有逐年上升趋势，据报道每年有一亿六千七百万人死于心血管病，AS是心脑血管事件发生的共同的病理生理基础，是引起心脑血管疾病和死亡的一个重要因素。近年来研究表明，AS的发生发展与氧化应激有着密切关系，AS发生的危险因素，如高胆固醇血症、糖尿病、高血压、吸烟等都会诱导内皮细胞、血管平滑肌细胞等产生过量氧自由基(ROS)，而这些ROS参与动脉粥样硬化从脂纹病变到斑块破裂的整个发展过程，并介导了血管内皮细胞、平滑肌细胞及单核巨噬细胞功能改变及损伤，同时又促进了炎症反应。因此寻找新型的针对性强的抗氧化剂仍然是防治动脉粥样硬化的首要任务。
β-榄香烯是榄香烯的主要活性成分，研究已表明，β-榄香烯具有抗氧化损伤作用，具有潜在的抗动脉粥样硬化作用。但是目前关于β-榄香烯衍生物在治疗动脉粥样硬化方面的研究却鲜有报道，因此通过对β-榄香烯结构进行优化，寻找新型的抗氧化损伤作用优于β-榄香烯的新化合物，对治疗动脉粥样硬化相关疾病具有重要的意义。
β-榄香烯属挥发油类，不溶于水，生物利用度很低，活性中等，鉴于其结构特点，对其衍生化的研究很有意义，而科研工作者前期的研究主要集中在合成β-榄香烯的13位含氮衍生物和醚类衍生物，结构改造较为单一，且未见有抗氧化活性衍生物报道。
发明内容
本发明公开了一种用β-榄香烯为原料制备β-榄香烯13位羧酸或酯类衍生物，药理学研究表明本发明的衍生物在抗氧化以及治疗动脉粥样硬化相关疾病中具有一定功效。本发明提供了一系列具有通式(I)或(II)结构特性的化合物的制备方法，通式(I)或(II)拓展了此类衍生物结构特征和结构范围。并进一步提供其中的抗氧化损伤作用优异，具有潜在治疗动脉粥样硬化疾病效果的化合物。
本发明的化合物结构式如下：
其中R1表示羧基、任意取代的C6-10芳基或C4-9芳杂环基，杂原子选自N、O或S，所述取代基选自卤素、OH、NO2、CF3、C1-3烷基或C1-3烷氧基；
R2表示任意取代的1,2-苯二基、1,3-苯二基、1,4-苯二基、1,8-萘二基或2,6-萘二基，所述取代基选自卤素、OH、NO2、CF3、C1-3烷基、C1-3烷氧基；
R2还表示-(CH2)n-，n＝0-10、-(CH2)a-CHX-(CH2)b-，X选自C1-3直链烷烃、-(CH2)a-(CH＝CH)c-(CH2)b-、-(CH2)a-(CCH3＝CH)c-(CH2)b-、-(CH2)a-(CH＝CCH3)c-(CH2)b-或-(CH2)a-(C≡C)c-(CH2)b-，其中a＝0-10,b＝0-10,c＝0-10。
其中R2优选表示任意取代的1,2-苯二基、1,3-苯二基或1,4-苯二基，所述取代基选自Cl、F、OH、NO2、CF3、CH3、OCH3；CH2、CH2CH2、CH2CH2CH2、CH2CH2CH2CH2、CH2CH2CH2CH2CH2、CH＝CH、CH＝CHCH2、CH＝CHCH2CH2、CH2CH＝CH、CH2CH＝CHCH2、CH2CH2CH＝CH、CH＝C(CH3)或CH＝C(CH3)CH2CH2。
R2更优选表示CH2、CH2CH2、CH＝CH、CH2CH2CH2或1,2-苯二基。
其中R1优选表示羧基、任意取代的苯基、吡啶基或呋喃基，所述取代基选自Cl、F、OH、NO2、CF3、CH3或OCH3。
R1更优选表示羧基、苯基、2-氯苯基、4-氯苯基、3-氟苯基、4-氟苯基、2-硝基苯基、4-硝基苯基、2-羟基苯基、4-甲基苯基、4-甲氧基苯基、吡啶基或呋喃基。
本发明更优选下列任一化合物或其药学上可接受的盐：
4-(13-β-榄香烯氧基)-4-氧代丁酸；
5-(13-β-榄香烯氧基)-4-氧代戊酸；
2-(13-β-榄香烯氧基羰基)苯甲酸；
13-(乙酸)-β-榄香醇酯；
13-(丙酸)-β-榄香醇酯；
13-(丁酸)-β-榄香醇酯；
13-(山梨酸)-β-榄香醇酯；
13-(苯甲酸)-β-榄香醇酯；
13-(4-甲基苯甲酸)-β-榄香醇酯；
13-(4-甲氧基苯甲酸)-β-榄香醇酯；
13-(2-氯苯甲酸)-β-榄香醇酯；
13-(4-氯苯甲酸)-β-榄香醇酯；
13-(3-氟苯甲酸)-β-榄香醇酯；
13-(4-氟苯甲酸)-β-榄香醇酯；
13-(4-硝基苯甲酸)-β-榄香醇酯；
13-(肉桂酸)-β-榄香醇酯；
13-(4-氟肉桂酸)-β-榄香醇酯；
13-(水杨酸)-β-榄香醇酯；
13-(烟酸)-β-榄香醇酯；
13-(异烟酸)-β-榄香醇酯；
13-(呋喃甲酸)-β-榄香醇酯；
丁二酸二(13-β-榄香醇)酯；
邻苯二甲酸二(13-β-榄香醇)酯。
下面是本发明中13位衍生物通式(I)或(II)所示化合物的制备方法。
通式(I)或(II)中所示化合物的制备，分别需经过13-β-榄香醇中间体。13-β-榄香醇的制备方法如反应一所示。在二氯甲烷与冰醋酸混合溶液中，β-榄香烯与次氯酸钠在冰浴条件下反应，制得13-氯代β-榄香烯。13-氯代β-榄香烯以无水DMF为溶剂与无水醋酸钠在加热条件下反应生成13-(乙酸)-β-榄香醇酯。13-(乙酸)-β-榄香醇酯经氢氧化钾水解即制得中间体13-β-榄香醇。
反应一：
通式(I)或(II)中含有羧基的衍生物可根据反应二制备。在DMAP和EDCI的催化下，13-β-榄香酸与相应的环二酸酐反应，即可制得相应产物。
反应二：
如反应三所示，在DMAP和EDCI的催化下，13-β-榄香酸与相应的脂肪族羧酸或芳香族羧酸反应，即可制得如通式(I)所示的其他相应衍生物。
反应三：
本发明化合物药学上可接受的盐，其特征在于：指常规的酸加成盐或碱加成盐，其具有与化合物同样的药学功效，且与合适的非毒性有机酸或无机酸或有机碱或无机碱成的盐。
本发明还公开了一种药物组合物，含本发明的化合物或其药学上可接受的盐，可以添加药学上可接受的载体制成常见的药用制剂，如片剂、胶囊、粉剂、糖浆、液剂、悬浮剂、针剂，可以加入香料、甜味剂、液体或固体填充料或稀释剂等常用的药物辅料。
本发明所述的化合物在临床上的给药方式可以采用口服、注射等方式。
本发明的化合物临床所用剂量为0.01mg～1000mg/天，也可根据病情的轻重或剂型的不同偏离此范围。
下面是本发明化合物的药效学试验及结果，药效学试验中所用化合物代号的化学结构见实施例：
一、体外抗氧化作用评价
取对数生长期的HUVEC细胞，以105个/mL的细胞悬液接种于6孔培养板中，培养24h后，吸弃培养液，空白组和损伤组加入新鲜的无血清DMEM高糖培养基，常规培养。给药组在此基础上分别加入浓度为5μmol/L或50μmol/L的各种药物，继续培养24h后，加入含H2O2终浓度为0.5mmol/L的DMEM无血清培养基，处理2h后，检测细胞内活性氧(ROS)，丙二醛(MDA)和超氧化物歧化酶(SOD)的含量。
ROS降低率＝(损伤组-给药组)/损伤组×100％
SOD增加率＝(给药组-模型组)/给药组×100％
MDA降低率＝(模型组-给药组)/给药组×100％。
实验结果见表1.
表1 β-榄香烯13位羧酸或酯类衍生物对氧化损伤内皮细胞氧化指标的影响(n＝3)
体外抗氧化活性评价显示，通过对β-榄香烯13位进行酯化修饰，所得衍生物对损伤后HUVEC表现出了较好的抗氧化活性。实验数据也进一步证实本发明提供了一种制备榄香烯衍生物抗氧化药物的有效方法。
二、本发明化合物对鹌鹑动脉粥样硬化模型动物的作用研究
1.鹌鹑动脉粥样硬化模型的建立与分组
健康雄性鹌鹑120只，重量110±20g/只，分笼饲养。定量给食(20g/只/天)，自由饮水，室温20℃-25℃，光照12小时/天。普通饲料喂养一周后，正常对照组饲以普通鹌鹑专用饲料，其余喂以高脂饲料(1％胆固醇、6％花生油、14％猪油和79％基础饲料)。建立鹌鹑动脉粥样硬化模型。鹌鹑高脂动脉粥样硬化造模3周后，喂以高脂饲料的鹌鹑按血清总胆固醇(TC)水平随机分为7组，每组15只。实验分组如下：①正常组；②模型组；③溶剂对照组；④阳性药组：辛伐他汀(6.5mg/kg)；⑤化合物23组(100mg/kg)；⑥化合物24(100mg/kg)。在喂以饲料的同时，每天上午分别灌胃给予相应药物，正常组和模型组给予等量的生理盐水。每周按体重调整给药剂量，给药7周。
在饲养过程中注意对动物精神状态、饮食、活动、粪便颜色及性状等一般情况的观察，并每周称量动物体重，检查饲喂高脂饲料及药物灌胃对动物身体状况的影响。
2.化合物23,24对动脉粥样硬化鹌鹑动脉壁形态学的影响
2.1 采集样本
末次给药后，禁食(不禁水)16h，鹌鹑处死，取出主动脉，用生理盐水冲洗血液以滤纸吸干。主动脉编号后用10％中性甲醛固定，进行HE染色，后观察动脉内膜的病变情况，按动脉粥样硬化病变分型法进行动脉病变程度分析。
2.2 实验结果见图1，由图可见，正常对照组动脉内膜光滑。模型组斑块融合成片，几乎覆盖整个管腔。溶剂对照组可见斑块明显凸起，融合成片。阳性药辛伐他汀及化合物23,24组动脉内膜增厚，但未见明显凸向管腔的AS斑块。对斑块形成有明显改善作用。提示化合物23,24对动脉粥样硬化疾病有良好的治疗作用。
附图说明
图1是化合物23、24对动脉粥样硬化鹌鹑动脉壁形态学的影响
具体实施方式
实施例1
中间体13-β-榄香醇(化合物1)的制备方法
将100mmolβ-榄香烯溶于20mL二氯甲烷和乙酸混合溶液中(V:V＝2:1)，冰浴条件下缓慢滴入含有180mmol活性氯的次氯酸钠溶液，冰浴反应4h。分出二氯甲烷层，水层以二氯甲烷萃取3次，合并二氯甲烷浓缩得淡黄色液体粗品，液体粗品溶于15mL无水N,N-二甲基甲酰胺(DMF)中,搅拌下加入200mmol无水醋酸钠,于100℃反应7h。反应液以200目硅胶硅胶抽滤,滤液加入15mL饱和食盐水,并以石油醚萃取3次。浓缩石油醚得黄色液体，以8mL甲醇和8mL氯仿的混合溶液溶解，加入200mmol氢氧化钾回流反应2h。过滤，滤液浓缩，以以石油醚：乙酸乙酯＝5:1(V:V)柱层析，得到无色液体产物，总产率为15％。
1H NMR(CDCl3,300MHz)δ:1.01(s,3H),1.41-1.67(m,6H),1.71(s,3H),1.97-2.05(m,2H),4.13(s,2H),4.59(s,1H),4.82(t,J＝1.7Hz,1H),4.88(s,1H),4.91-4.94(m,2H),5.05(d,J＝1.3Hz,1H),5.81(dd,J1＝17.8Hz,J2＝10.5Hz,1H).
13C NMR(CDCl3,300MHz)δ:153.7,150.0,147.4,112.1,109.9,107.9,65.1,52.7,41.4,39.8,39.7,33.2,27.2,24.7,16.5.
实施例2
4-(13-β-榄香烯氧基)-4-氧代丁酸(化合物2)的制备方法
将3mmol 13-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol 4-二甲氨基吡啶(DMAP)、0.3mmol 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)和3.3mmol丁二酸酐，常温反应10h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝8:1(V:V)柱层析，得到无色液体产物，产率为60％。
1H NMR(CDCl3,300MHz)δ:1.01(s,3H),1.41-1.68(m,6H),1.71(s,3H),1.99-2.04(m,2H),2.64-2.74(m,4H),4.59(s,1H),4.62(s,2H),4.83(s,1H),4.88(s,1H),4.93(d,J＝4.0Hz,1H),5.01(s,1H),5.05(s,1H),5.81(dd,J1＝17.8Hz,J2＝10.5Hz,1H).
13C NMR(CDCl3,300MHz)δ:177.7,171.8,150.0,148.2,147.4,112.3,111.2,110.0,66.5,52.7,41.8,39.8,39.7,33.0,28.9,28.8,27.1,24.8,16.6.
实施例3
5-(13-β-榄香烯氧基)-5-氧代戊酸(化合物3)的制备方法
将3mmol13-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmolEDCI和3.3mmol戊二酸酐，常温反应10h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝8:1(V:V)柱层析，得到无色液体产物，产率为64％。
1H NMR(CDCl3,300MHz)δ:1.01(s,3H),1.42-1.68(m,6H),1.71(s,3H),1.93-2.04(m,4H),2.45(t,J＝7.2Hz,4H),4.60(s,3H),4.83(s,1H),4.88(s,1H),4.92(d,J＝4.1Hz,1H),5.01(s,1H),5.04(s,1H),5.81(dd,J1＝17.8Hz,J2＝10.4Hz,1H).
13C NMR(CDCl3,300MHz)δ:178.9,172.6,150.0,148.3,147.3,112.3,111.1,110.0,66.2,58.7,41.8,39.8,39.7,33.2,33.1,33.0,27.0,24.8,19.8,16.6.
实施例4
2-(13-β-榄香烯氧基羰基)苯甲酸(化合物4)的制备方法
将3mmol 13-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmolEDCI和3.3mmol邻苯二甲酸酐，常温反应10h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝8:1(V:V)柱层析，得到无色液体产物，产率为72％。
1H NMR(CDCl3,300MHz)δ:0.98(s,3H),1.38-1.63(m,6H),1.68(s,3H),1.97-2.07(m,2H),4.56(s,1H),4.80(s,1H),4.82(s,2H),4.85(s,1H),4.90(d,J＝4.7Hz,1H),5.04(s,1H),5.13(s,1H),5.78(dd,J1＝17.7Hz,J2＝10.5Hz,1H),7.51-7.61(m,2H),7.69-7.72(m,1H),7.88-7.91(m,1H).
13C NMR(CDCl3,300MHz)δ:172.1,167.9,150.0,147.9,147.4,133.0,131.9,130.9,129.9,128.9,128.8,112.3,111.7,110.0,67.7,52.7,41.8,39.8,39.7,33.0,27.1,24.7,16.6.
实施例5
13-(乙酸)-β-榄香醇酯(化合物5)的制备方法
将3mmol 13-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmolEDCI和4mmol冰醋酸，常温反应12h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝300:1(V:V)柱层析，得到无色液体产物,产率为66％。
1H NMR(CDCl3,300MHz)δ:0.94(s,3H),1.35-1.58(m,6H),1.64(s,3H),1.92-1.97(m,2H),2.02(s,3H),4.51(s,3H),4.76(s,1H),4.81(s,1H),4.86(d,J＝4.3Hz,1H),4.94(s,1H),4.98(s,1H),5.74(dd,J1＝17.7Hz,J2＝10.5Hz,1H).
13C NMR(CDCl3,300MHz)δ:169.7,149.0,147.4,146.3,111.3,109.9,109.0,65.1,51.7,40.9,38.8,38.7,32.1,26.1,23.7,20.0,15.6.
实施例6
13-(丙酸)-β-榄香醇酯(化合物6)的制备方法
将3mmol 13-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmolEDCI和4mmol丙酸，常温反应12h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝300:1(V:V)柱层析，得到无色液体产物，产率为61％。
1H NMR(CDCl3,300MHz)δ:0.94(s,3H),1.10(t,J＝7.6Hz,3H),1.36-1.58(m,6H),1.64(s,3H),1.91-1.97(m,2H),2.31(q,J＝7.5Hz,2H),4.52(s,3H),4.75(s,1H),4.81(s,1H),4.85(d,J＝4.0Hz,1H),4.93(s,1H),4.98(s,1H),5.74(dd,J1＝17.8Hz,J2＝10.5Hz,1H).
13C NMR(CDCl3,300MHz)δ:173.1,149.0,147.6,146.3,111.3,109.8,109.0,65.0,51.7,40.9,38.8,38.7,32.1,26.7,26.1,23.7,15.6,8.1.
实施例7
13-(丁酸)-β-榄香醇酯(化合物7)的制备方法
将3mmol 13-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmolEDCI和4mmol丁酸，常温反应12h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝300:1(V:V)柱层析，得到无色液体产物，产率为61％。
1H NMR(CDCl3,300MHz)δ:0.89(t,J＝7.5Hz,3H),0.93(s,3H),1.35-1.62(m,8H),1.64(s,3H),1.91-1.96(m,2H),2.26(t,J＝7.5Hz,2H),2.68(s,3H),4.75(s,1H),4.81(s,1H),4.85(d,J＝4.2Hz,1H),4.93(s,1H),4.98(s,1H),5.74(dd,J1＝17.8Hz,J2＝10.6Hz,1H).
13C NMR(CDCl3,300MHz)δ:172.3,149.0,147.6,146.4,111.3,109.8,109.0,64.9,51.8,40.9,38.8,38.7,35.3,32.1,26.1,23.7,17.5,15.6,12.7.
实施例8
13-(山梨酸)-β-榄香醇酯(化合物8)的制备方法
将3mmol 13-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmolEDCI和4mmol山梨酸，常温反应12h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝300:1(V:V)柱层析，得到无色液体产物，产率为70％。
1H NMR(CDCl3,300MHz)δ:1.01(s,3H),1.43-1.67(m,6H),1.71(s,3H),1.85(d,J＝5.4Hz,3H),1.99-2.04(m,2H),4.59(s,1H),4.66(s,2H),4.82(s,1H),4.88(s,1H),4.92(d,J＝4.3Hz,1H),5.01(s,1H),5.07(s,1H),5.77-5.89(m,2H),6.10-6.25(m,2H),7.24-7.32(m,1H).
13C NMR(CDCl3,300MHz)δ:167.0,150.1,148.7,147.4,145.3,139.5,129.8,118.8,112.2,110.8,110.0,65.9,52.7,41.9,39.8,39.7,33.1,27.1,24.8,18.6,16.6.
实施例9
13-(苯甲酸)-β-榄香醇酯(化合物9)的制备方法
将3mmol 13-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmolEDCI和4mmol苯甲酸，常温反应14h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝300:1(V:V)柱层析，得到无色液体产物，产率为73％。
1H NMR(CDCl3,300MHz)δ:1.02(s,3H),1.45-1.69(m,6H),1.71(s,3H),2.01-2.06(m,1H),2.11-2.16(m,1H),4.59(s,1H),4.84(s,3H),4.88(s,1H),4.93(d,J＝4.2Hz,1H),5.07(s,1H),5.16(s,1H),5.82(dd,J1＝17.0Hz,J2＝10.5Hz,1H),7.45(t,J＝7.5Hz,2H),7.57(t,J＝7.5Hz,1H),8.06-8.08(m,2H).
13C NMR(CDCl3,300MHz)δ:166.3,150.0,148.5,147.4,133.0,130.3,129.6,128.4,112.3,111.2,110.0,66.6,52.7,42.1,39.9,39.8,33.2,27.1,24.8,16.6.
实施例10
13-(4-甲基苯甲酸)-β-榄香醇酯(化合物10)的制备方法
将3mmol 13-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmolEDCI和4mmol4-甲基苯甲酸，常温反应14h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝300:1(V:V)柱层析，得到无色液体产物，产率为67％。
1H NMR(CDCl3,300MHz)δ:1.01(s,3H),1.48-1.68(m,6H),1.71(s,3H),2.00-2.05(m,1H),2.10-2.16(m,1H),2.41(s,3H),4.59(s,1H),4.82(s,3H),4.88(s,1H),4.92(d,J＝4.4Hz,1H),5.06(s,1H),5.15(s,1H),5.81(dd,J1＝17.7Hz,J2＝10.5Hz,1H),7.24(d,J＝7.8Hz,2H),7.95(d,J＝7.8Hz,2H).
13C NMR(CDCl3,300MHz)δ:166.3,150.0,148.6,147.4,143.7,129.6,129.1,112.3,111.0,110.1,66.4,52.8,42.1,39.9,39.8,33.2,27.1,24.8,21.7,16.6.
实施例11
13-(4-甲氧基苯甲酸)-β-榄香醇酯(化合物11)的制备方法
将3mmol 13-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmolEDCI和4mmol4-甲氧基苯甲酸，常温反应14h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝40:1(V:V)柱层析，得到无色液体产物，产率为65％。
1H NMR(CDCl3,300MHz)δ:1.01(s,3H),1.44-1.68(m,6H),1.71(s,3H),2.00-2.19(m,2H),3.86(s,3H),4.59(s,1H),4.81(s,2H),4.83(s,1H),4.88(s,1H),4.92(d,J＝7.3Hz,1H),5.05(s,1H),5.14(s,1H),5.82(dd,J1＝17.7Hz,J2＝10.5Hz,1H),6.92(d,J＝8.9Hz,2H),8.02(d,J＝8.9Hz,2H).
13C NMR(CDCl3,300MHz)δ:163.4,150.0,148.7,147.4,131.7,113.7,112.3,110.9,110.0,66.3,55.4,52.7,42.1,39.9,39.8,33.2,29.7,27.1,24.8,16.6.
实施例12
13-(2-氯苯甲酸)-β-榄香醇酯(化合物12)的制备方法
将3mmol 13-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmolEDCI和4mmol2-氯苯甲酸，常温反应14h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝200:1(V:V)柱层析，得到无色液体产物,产率为60％。
1H NMR(CDCl3,300MHz)δ:1.02(s,3H),1.45-1.68(m,6H),1.71(s,3H),2.00-2.05(m,1H),2.11-2.17(m,1H),4.59(s,1H),4.83(s,1H),4.85(s,2H),4.88(s,1H),4.93(d,J＝4.2Hz,1H),5.08(s,1H),5.18(s,1H),5.82(dd,J1＝17.8Hz,J2＝10.5Hz,1H),7.29-7.35(m,1H),7.39-7.48(m,2H),7.84(dd,J1＝7.5Hz,J2＝1.1Hz,1H).
13C NMR(CDCl3,300MHz)δ:165.4,150.0,148.1,147.4,132.5,131.4,131.1,126.6,112.3,111.7,110.0,67.3,52.8,41.8,39.8,39.7,33.1,27.1,24.8,16.6.
实施例13
13-(4-氯苯甲酸)-β-榄香醇酯(化合物13)的制备方法
将3mmol 13-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmolEDCI和4mmol4-氯苯甲酸，常温反应14h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝200:1(V:V)柱层析，得到无色液体产物,产率为72％。
1H NMR(CDCl3,300MHz)δ:1.01(s,3H),1.45-1.68(m,6H),1.71(s,3H),2.00-2.11(m,2H),4.59(s,1H),4.83(s,3H),4.88(s,1H),4.93(d,J＝3.8Hz,1H),5.07(s,1H),5.14(s,1H),5.82(dd,J1＝17.7Hz,J2＝10.5Hz,1H),7.42(d,J＝8.6Hz,2H),8.00(d,J＝8.6Hz,2H).
13C NMR(CDCl3,300MHz)δ:165.4,150.0,148.3,147.3,139.5,131.0,128.8,112.3,111.4,110.1,66.8,52.7,42.1,39.8,39.7,33.2,27.1,24.8,16.6.
实施例14
13-(3-氟苯甲酸)-β-榄香醇酯(化合物14)的制备方法
将3mmol 13-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmolEDCI和4mmol3-氟苯甲酸，常温反应14h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝200:1(V:V)柱层析，得到无色液体产物,产率为66％。
1H NMR(CDCl3,300MHz)δ:1.02(s,3H),1.45-1.68(m,6H),1.71(s,3H),2.00-2.17(m,2H),4.59(s,1H),4.84(s,3H),4.89(s,1H),4.93(d,J＝4.3Hz,1H),5.08(s,1H),5.15(s,1H),5.82(dd,J1＝17.8Hz,J2＝10.4Hz,1H),7.24-7.30(m,1H),7.39-7.47(m,1H),7.74(d,J＝7.7Hz,1H),7.86(d,J＝7.7Hz,1H).
13C NMR(CDCl3,300MHz)δ:164.2,150.0,148.2,147.3,130.1,130.0,125.4,125.3,120.2,119.9,116.7,116.4,112.3,111.5,110.1,66.9,52.7,42.1,39.8,39.7,33.2,27.1,24.8,16.6.
实施例15
13-(4-氟苯甲酸)-β-榄香醇酯(化合物15)的制备方法
将3mmol 13-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmolEDCI和4mmol4-氟苯甲酸，常温反应14h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝200:1(V:V)柱层析，得到无色液体产物，产率为66％。
1H NMR(CDCl3,300MHz)δ:1.01(s,3H),1.49-1.68(m,6H),1.71(s,3H),2.00-2.11(m,2H),4.59(s,1H),4.82(s,3H),4.88(s,1H),4.93(d,J＝4.1Hz,1H),5.07(s,1H),5.14(s,1H),5.81(dd,J1＝17.7Hz,J2＝10.5Hz,1H),7.09-7.15(m,2H),8.06-8.11(m,2H).
13C NMR(CDCl3,300MHz)δ:165.3,150.0,148.4,147.3,132.2,132.1,115.7,115.4,112.3,111.3,110.1,66.7,52.7,42.1,39.8,39.7,33.2,27.1,24.8,16.6.
实施例16
13-(4-硝基苯甲酸)-β-榄香醇酯(化合物16)的制备方法
将3mmol 13-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmolEDCI和4mmol4-硝基苯甲酸，常温反应14h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝200:1(V:V)柱层析，得到无色液体产物，产率为58％。
1H NMR(CDCl3,300MHz)δ:1.02(s,3H),1.46-1.68(m,6H),1.71(s,3H),2.01-2.14(m,2H),4.59(s,1H),4.84(s,1H),4.88(s,3H),4.93(d,J＝3.7Hz,1H),5.11(s,1H),5.17(s,1H),5.82(dd,J1＝17.7Hz,J2＝10.5Hz,1H),8.22(d,J＝8.9Hz,2H),8.30(d,J＝8.9Hz,2H).
13C NMR(CDCl3,300MHz)δ:164.4,150.6,149.8,147.8,147.3,135.6,130.7,123.6,112.3,112.0,111.2,67.5,52.7,42.1,39.8,39.7,33.1,27.1,24.8,16.6.
实施例17
13-(肉桂酸)-β-榄香醇酯(化合物17)的制备方法
将3mmol 13-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmolEDCI和4mmol肉桂酸，常温反应14h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝200:1(V:V)柱层析，得到无色液体产物，产率为74％。
1H NMR(CDCl3,300MHz)δ:0.95(s,3H),1.43-1.59(m,6H),1.64(s,3H),1.93-2.02(m,2H),4.53(s,1H),4.65(s,2H),4.76(s,1H),4.81(s,1H),4.86(d,J＝5.5Hz,1H),4.98(s,1H),5.05(s,1H),5.75(dd,J1＝17.8Hz,J2＝10.4Hz,1H),6.41(d,J＝16.0Hz,1H),7.31-7.33(m,3H),7.45-7.47(m,2H),7.64(d,J＝16.0Hz,1H).
13C NMR(CDCl3,300MHz)δ:165.6,149.0,147.5,146.4,144.0,133.4,129.3,127.9,127.1,117.0,111.3,110.1,109.0,65.2,51.7,40.9,38.8,38.7,32.1,26.1,23.8,15.6.
实施例18
13-(4-氟肉桂酸)-β-榄香醇酯(化合物18)的制备方法
将3mmol 13-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmolEDCI和4mmol 4-氟肉桂酸，常温反应14h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝200:1(V:V)柱层析，得到无色液体产物，产率为70％。
1H NMR(CDCl3,300MHz)δ:1.02(s,3H),1.45-1.69(m,6H),1.71(s,3H),2.00-2.08(m,2H),4.60(s,1H),4.72(s,2H),4.83(s,1H),4.88(s,1H),4.93(d,J＝4.6Hz,1H),5.05(s,1H),5.11(s,1H),5.82(dd,J1＝17.8Hz,J2＝10.4Hz,1H),6.40(d,J＝16.0Hz,1H),7.08(t,J＝8.6Hz,2H),7.50-7.55(m,2H),7.67(d,J＝16.0Hz,1H).
13C NMR(CDCl3,300MHz)δ:165.6,150.0,148.5,147.4,143.7,130.0,129.9,117.7,116.2,115.9,112.3,111.1,110.0,66.3,52.7,41.9,39.8,39.7,33.1,27.1,24.8,16.6.
实施例19
13-(水杨酸)-β-榄香醇酯(化合物19)的制备方法
将3mmol 13-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmol EDCI和4mmol水杨酸，常温反应14h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝40:1(V:V)柱层析，得到无色液体产物，产率为75％。
1H NMR(CDCl3,300MHz)δ:1.02(s,3H),1.45-1.68(m,6H),1.71(s,3H),2.01-2.17(m,2H),4.60(s,1H),4.84(s,1H),4.86(s,2H),4.89(s,1H),4.93(d,J＝4.0Hz,1H),5.10(s,1H),5.16(s,1H),5.82(dd,J1＝17.7Hz,J2＝10.6Hz,1H),6.89(t,J＝8.4Hz,1H),6.98(d,J＝8.0Hz,1H),7.44-7.49(m,1H),7.87(dd,J1＝8.0Hz,J2＝1.6Hz,1H),10.76(s,1H).
13C NMR(CDCl3,300MHz)δ:169.8,161.8,149.9,147.8,147.3,135.8,129.8,119.2,117.7,112.5,112.3,111.9,110.1,66.9,52.7,42.0,39.8,39.7,33.2,27.1,24.8,16.6.
实施例20
13-(烟酸)-β-榄香醇酯(化合物20)的制备方法
将3mmol 13-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmol EDCI和4mmol烟酸，常温反应20h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝40:1(V:V)柱层析，得到无色液体产物，产率为58％。
1H NMR(CDCl3,300MHz)δ:1.02(s,3H),1.45-1.68(m,6H),1.71(s,3H),2.01-2.15(m,2H),4.59(s,1H),4.83(s,2H),4.87(s,2H),4.88(s,1H),4.93(d,J＝5.1Hz,1H),5.09(s,1H),5.16(s,1H),5.82(dd,J1＝17.7Hz,J2＝10.4Hz,1H),7.41(dd,J1＝7.6Hz,J2＝4.6Hz,1H),8.32(d,J＝7.8Hz,1H),8.78(d,J＝3.8Hz,1H),9.26(s,1H).
13C NMR(CDCl3,300MHz)δ:164.9,153.5,150.9,149.9,148.0,147.3,137.1,123.3,112.3,111.7,110.1,67.0,52.7,42.0,39.8,39.7,33.1,27.1,24.8,16.6.
实施例21
13-(异烟酸)-β-榄香醇酯(化合物21)的制备方法
将3mmol 13-β-榄香醇或14-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmol EDCI和4mmol异烟酸，常温反应20h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝40:1(V:V)柱层析，得到无色液体产物，产率为72％。
1H NMR(CDCl3,300MHz)δ:1.02(s,3H),1.46-1.68(m,6H),1.71(s,3H),2.01-2.15(m,2H),4.59(s,1H),4.84(s,1H),4.87(s,2H),4.89(s,1H),4.93(d,J＝4.0Hz,1H),5.10(s,1H),5.16(s,1H),5.81(dd,J1＝17.8Hz,J2＝10.5Hz,1H),7.86(d,J＝5.7Hz,2H),8.79(d,J＝5.7Hz,2H).
13C NMR(CDCl3,300MHz)δ:164.8,150.6,149.9,147.8,147.3,137.4,122.8,112.3,111.9,110.1,67.3,52.7,42.1,39.8,39.7,33.2,27.1,24.8,16.6.
实施例22
13-(呋喃甲酸)-β-榄香醇酯(化合物22)的制备方法
将3mmol 13-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.3mmol EDCI和4mmol呋喃甲酸，常温反应15h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝100:1(V:V)柱层析，得到无色液体产物，产率为60％。
1H NMR(CDCl3,300MHz)δ:1.01(s,3H),1.45-1.67(m,6H),1.71(s,3H),1.98-2.16(m,2H),4.59(s,1H),4.81(s,2H),4.82(s,1H),4.88(s,1H),4.92(d,J＝5.0Hz,1H),5.06(s,1H),5.14(s,1H),5.81(dd,J1＝17.7Hz,J2＝10.5Hz,1H),6.51-6.52(m,1H),7.19(d,J＝3.5Hz,1H),7.58(d,J＝0.7Hz,1H).
13C NMR(CDCl3,300MHz)δ:158.4,150.0,148.1,147.3,146.4,117.9,112.3,111.8,111.6,110.0,66.0,52.7,42.0,39.8,39.7,33.1,29.7,27.1,24.7,16.6.
实施例23
丁二酸二(13-β-榄香醇)酯(化合物23)的制备方法
将6mmol 13-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.6mmol EDCI和3mmol丁二酸酐，常温反应8h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝100:1(V:V)柱层析，得到无色液体产物，产率为78％。
1H NMR(CDCl3,300MHz)δ:0.94(s,6H),1.35-1.61(m,12H),1.64(s,6H),1.92-1.97(m,4H),2.62(s,4H),4.52(s,2H),4.54(s,4H),4.75(s,2H),4.81(s,2H),4.85(d,J＝4.1Hz,2H),4.94(s,2H),4.98(s,2H),5.74(dd,J1＝17.8Hz,J2＝10.5Hz,2H).
13C NMR(CDCl3,300MHz)δ:170.9,149.0,147.3,146.3,111.3,110.0,109.0,65.4,51.7,40.8,38.8,38.7,30.1,28.2,26.1,23.8,15.6.
实施例24
邻苯二甲酸二(13-β-榄香醇)酯(化合物24)的制备方法
将6mmol 13-β-榄香醇溶于10mL无水二氯甲烷中，加入0.3mmol DMAP、0.6mmol EDCI和3mmol邻苯二甲酸酐，常温反应10h。反应液以10％盐酸洗涤3次，浓缩二氯甲烷层得淡黄色液体。以石油醚：乙酸乙酯＝100:1(V:V)柱层析，得到无色液体产物,产率为72％。
1H NMR(CDCl3,300MHz)δ:0.93(s,6H),1.40-1.58(m,12H),1.63(s,6H),1.92-1.97(m,4H),4.51(s,2H),4.72(s,4H),4.75(s,2H),4.80(s,2H),4.85(d,J＝4.2Hz,2H),4.97(s,2H),5.05(s,2H),5.75(dd,J1＝17.7Hz,J2＝10.5Hz,2H),7.47-7.50(m,2H),7.67-7.70(m,2H).
13C NMR(CDCl3,300MHz)δ:166.2,149.0,147.0,146.3,131.1,130.1,127.9,111.3,110.3,109.0,66.3,51.7,40.8,38.8,38.7,32.0,26.1,23.8,15.6.

Claims (8)

1.通式(I)或(II)的化合物或其药学上可接受的盐：
其中R1表示羧基、任意取代的C6-10芳基或C4-9芳杂环基，杂原子选自N、O或S，所述取代基选自卤素、OH、NO2、CF3、C1-3烷基或C1-3烷氧基；
R2表示任意取代的1,2-苯二基、1,3-苯二基、1,4-苯二基、1,8-萘二基或2,6-萘二基，所述取代基选自卤素、OH、NO2、CF3、C1-3烷基、C1-3烷氧基；
R2还表示-(CH2)n-，n＝0-10、-(CH2)a-CHX-(CH2)b-，X选自C1-3直链烷烃、-(CH2)a-(CH＝CH)c-(CH2)b-、-(CH2)a-(CCH3＝CH)c-(CH2)b-、-(CH2)a-(CH＝CCH3)c-(CH2)b-或-(CH2)a-(C≡C)c-(CH2)b-，其中a＝0-10,b＝0-10,c＝0-10。
2.权利要求1的化合物或其药学上可接受的盐，其中R2表示任意取代的1,2-苯二基、1,3-苯二基或1,4-苯二基，所述取代基选自Cl、F、OH、NO2、CF3、CH3、OCH3；CH2、CH2CH2、CH2CH2CH2、CH2CH2CH2CH2、CH2CH2CH2CH2CH2、CH＝CH、CH＝CHCH2、CH＝CHCH2CH2、CH2CH＝CH、CH2CH＝CHCH2、CH2CH2CH＝CH、CH＝C(CH3)或CH＝C(CH3)CH2CH2。
3.权利要求2的化合物或其药学上可接受的盐，其中R2表示CH2、CH2CH2、CH＝CH、CH2CH2CH2或1,2-苯二基。
4.权利要求1的化合物或其药学上可接受的盐，其中R1表示羧基、任意取代的苯基、吡啶基或呋喃基，所述取代基选自Cl、F、OH、NO2、CF3、CH3或OCH3。
5.权利要求4的化合物或其药学上可接受的盐，其中R1表示羧基、苯基、2-氯苯基、4-氯苯基、3-氟苯基、4-氟苯基、2-硝基苯基、4-硝基苯基、2-羟基苯基、4-甲基苯基、4-甲氧基苯基、吡啶基或呋喃基。
6.权利要求1的化合物或其药学上可接受的盐，是下列任一化合物或其药学上可接受的盐：
4-(13-β-榄香烯氧基)-4-氧代丁酸；
5-(13-β-榄香烯氧基)-4-氧代戊酸；
2-(13-β-榄香烯氧基羰基)苯甲酸；
13-(乙酸)-β-榄香醇酯；
13-(丙酸)-β-榄香醇酯；
13-(丁酸)-β-榄香醇酯；
13-(山梨酸)-β-榄香醇酯；
13-(苯甲酸)-β-榄香醇酯；
13-(4-甲基苯甲酸)-β-榄香醇酯；
13-(4-甲氧基苯甲酸)-β-榄香醇酯；
13-(2-氯苯甲酸)-β-榄香醇酯；
13-(4-氯苯甲酸)-β-榄香醇酯；
13-(3-氟苯甲酸)-β-榄香醇酯；
13-(4-氟苯甲酸)-β-榄香醇酯；
13-(4-硝基苯甲酸)-β-榄香醇酯；
13-(肉桂酸)-β-榄香醇酯；
13-(4-氟肉桂酸)-β-榄香醇酯；
13-(水杨酸)-β-榄香醇酯；
13-(烟酸)-β-榄香醇酯；
13-(异烟酸)-β-榄香醇酯；
13-(呋喃甲酸)-β-榄香醇酯；
丁二酸二(13-β-榄香醇)酯；
邻苯二甲酸二(13-β-榄香醇)酯。
7.药物组合物，其中含有权利要求1的化合物或其药学上可接受的盐及药学上可接受的载体。
8.权利要求1至6中任一项的化合物或其药学上可接受的盐用于制备治疗动脉粥样硬化的疾病的用途。
CN201410376842.7A 2014-08-01 2014-08-01 β-榄香烯13位衍生物及其治疗动脉粥样硬化的用途 Pending CN104130124A (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201410376842.7A CN104130124A (zh) 2014-08-01 2014-08-01 β-榄香烯13位衍生物及其治疗动脉粥样硬化的用途
PCT/CN2015/075315 WO2016015479A1 (zh) 2014-08-01 2015-03-27 β-榄香烯13位衍生物及其治疗动脉粥样硬化的用途

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201410376842.7A CN104130124A (zh) 2014-08-01 2014-08-01 β-榄香烯13位衍生物及其治疗动脉粥样硬化的用途

Publications (1)

Publication Number Publication Date
CN104130124A true CN104130124A (zh) 2014-11-05

Family

ID=51803031

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201410376842.7A Pending CN104130124A (zh) 2014-08-01 2014-08-01 β-榄香烯13位衍生物及其治疗动脉粥样硬化的用途

Country Status (2)

Country Link
CN (1) CN104130124A (zh)
WO (1) WO2016015479A1 (zh)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016015479A1 (zh) * 2014-08-01 2016-02-04 大连远大医药科技开发有限公司 β-榄香烯13位衍生物及其治疗动脉粥样硬化的用途
CN106866418A (zh) * 2017-01-19 2017-06-20 石药集团远大(大连)制药有限公司 β‑榄香烯二聚体衍生物、其制备方法及其用途
CN106866572A (zh) * 2017-02-07 2017-06-20 石药集团远大(大连)制药有限公司 一氧化氮供体型β‑榄香烯衍生物及其制备方法和用途
CN106928074A (zh) * 2017-01-19 2017-07-07 石药集团远大(大连)制药有限公司 异丙醇胺取代β‑榄香烯衍生物及其制备方法和用途
CN110627615A (zh) * 2019-09-29 2019-12-31 杭州师范大学 β-榄香烯氧化物及制备方法和用途
WO2023061095A1 (zh) * 2021-10-11 2023-04-20 杭州师范大学 14-氯-β-榄香烯一氧化氮供体型衍生物及其制备和应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1844084A (zh) * 2006-05-10 2006-10-11 沈阳药科大学 β－榄香烯氨基酸或羧酸衍生物及制备方法和用途
CN103284978A (zh) * 2013-06-17 2013-09-11 大连远大医药科技开发有限公司 β-榄香烯及其衍生物在抗动脉粥样硬化中的用途

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104130124A (zh) * 2014-08-01 2014-11-05 大连远大医药科技开发有限公司 β-榄香烯13位衍生物及其治疗动脉粥样硬化的用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1844084A (zh) * 2006-05-10 2006-10-11 沈阳药科大学 β－榄香烯氨基酸或羧酸衍生物及制备方法和用途
CN103284978A (zh) * 2013-06-17 2013-09-11 大连远大医药科技开发有限公司 β-榄香烯及其衍生物在抗动脉粥样硬化中的用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JICHAO CHEN ET AL: "Design, synthesis and antioxidant activity evaluation of novel β-elemene derivatives", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016015479A1 (zh) * 2014-08-01 2016-02-04 大连远大医药科技开发有限公司 β-榄香烯13位衍生物及其治疗动脉粥样硬化的用途
CN106866418A (zh) * 2017-01-19 2017-06-20 石药集团远大(大连)制药有限公司 β‑榄香烯二聚体衍生物、其制备方法及其用途
CN106928074A (zh) * 2017-01-19 2017-07-07 石药集团远大(大连)制药有限公司 异丙醇胺取代β‑榄香烯衍生物及其制备方法和用途
CN106866418B (zh) * 2017-01-19 2018-07-17 石药集团远大(大连)制药有限公司 β-榄香烯二聚体衍生物、其制备方法及其用途
CN106928074B (zh) * 2017-01-19 2018-12-18 石药集团远大(大连)制药有限公司 异丙醇胺取代β-榄香烯衍生物及其制备方法和用途
CN106866572A (zh) * 2017-02-07 2017-06-20 石药集团远大(大连)制药有限公司 一氧化氮供体型β‑榄香烯衍生物及其制备方法和用途
CN106866572B (zh) * 2017-02-07 2018-03-09 石药集团远大(大连)制药有限公司 一氧化氮供体型β‑榄香烯衍生物及其制备方法和用途
CN110627615A (zh) * 2019-09-29 2019-12-31 杭州师范大学 β-榄香烯氧化物及制备方法和用途
CN110627615B (zh) * 2019-09-29 2022-11-29 杭州师范大学 β-榄香烯氧化物及制备方法和用途
WO2023061095A1 (zh) * 2021-10-11 2023-04-20 杭州师范大学 14-氯-β-榄香烯一氧化氮供体型衍生物及其制备和应用

Also Published As

Publication number Publication date
WO2016015479A1 (zh) 2016-02-04

Similar Documents

Publication Publication Date Title
CN104130124A (zh) β-榄香烯13位衍生物及其治疗动脉粥样硬化的用途
Qiao et al. Chalcone–benzoxaborole hybrid molecules as potent antitrypanosomal agents
Bytyqi-Damoni et al. Novel carvacrol based new oxypropanolamine derivatives: Design, synthesis, characterization, biological evaluation, and molecular docking studies
KR900005518B1 (ko) 퓨로-(3,4-c)-피리딘 유도체의 제조방법
CN104119221A (zh) β-榄香烯14位衍生物及其治疗动脉粥样硬化的用途
CN106905313A (zh) 一氧化氮供体型原小檗碱类衍生物及其制备方法和用途
CN101544579B (zh) 4-(2-乙酰氧基苯甲酰)氨基丁酸及其酯类衍生物的用途及制备方法
CN107162921A (zh) 一类新型苯氧乙酸衍生物、其制备方法及其作为药物的用途
JP4991537B2 (ja) シス−１，２−置換スチルベン誘導体、および糖尿病の治療および／または予防のための薬剤の製造におけるそれらの使用
CN101724007A (zh) 齐墩果酸衍生物及其作为α-葡萄糖苷酶抑制剂的用途
CN104586842B (zh) 一种抗癌活性吲哚衍生物、合成方法及其用途
CN101974016A (zh) 酰胺类化合物及其制备方法和用途
CN106866418B (zh) β-榄香烯二聚体衍生物、其制备方法及其用途
CN115108964A (zh) 一种苯酞类衍生物、制备方法及应用
CN111393372B (zh) 一种苯并咪唑衍生物及其制备方法和用途
CN112707840B (zh) 含多炔基的α,β-二氨基酸酯衍生物类化合物及其制备和应用
CN109627199B (zh) 一种光学活性黄皮酰胺酮衍生物及其应用
CN106397207A (zh) 树豆酮酸a结构类似物、其组合物及其在药物中的应用
CN107686463B (zh) 一类查尔酮芳氧乙酰胺化合物、制备方法及其应用
CN101787029A (zh) 长链烷基黄连碱卤酸盐衍生物、合成方法及用途
CN111393421A (zh) 丁烯酸内酯类衍生物及其制备方法与应用
JP7210605B2 (ja) エモジンスクシニルエステル系化合物およびその調製方法と用途
CN107162913A (zh) 一类新型氘代苯丙酸衍生物、其制备方法及其作为药物的用途
CN112920118B (zh) 一种京尼平氨基酸衍生物及其制备方法和用途
CN108003001B (zh) 化合物Cur20及其制备方法与应用

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20141105